We are searching for genetic linkage between genes that contribute to the predisposition to alcoholism and related behaviors using over 400 highly polymorphic DNA marker loci that span the human genome. To date, we have completed over 150,000 locus typings, primarily on American Indians and Finns. One finding concerns a dinucleotide repeat polymorphism in the D2 dopamine receptor gene on chromosome 12. In 459 Southwestern Indians, concordant unaffected sibpairs share identical by descent marker alleles more frequently than expected (P<0.008). Despite this evidence for linkage, the alleles at this locus are not significantly associated with alcoholism. This implies that the effect is due to a closely linked gene. We have also looked for genetic linkage between alcoholism and typings at 463 autosomal microsatellite using 125 of the Southwestern Indian subjects. The typings were conducted as a part of an NIDDK collaborative study on diabetes. These analyses revealed 22 loci with p<5% and 7 loci p<1%. Interestingly, 3 chromosome 4 loci that map along with the alcohol dehydrogenase gene cluster (ADH), have p-values below 1%. There are well known alleles in the ADH gene family that enhance catalytic activity. Since high ADH activity lowers tolerance to alcohol, carriers of these alleles are less likely to be alcoholic. Thus, variants at ADH exert a protective effect, where they influence alcoholism vulnerability. Populations, such as this Southwestern Indian tribe, with a high prevalence of alcoholism may reveal other protective factors. We are now investigating Y chromosome DNA variability a sample of 270 Finns. Variability in the TPQ personality scale were investigated along with alcohol dependence and antisocial personality disorder (ASPD). Reward dependence was associated with 5 related Y chromosome types (p<0.05) that are relatively common. With regard to alcohol dependence and ASPD, we find a significant association between 3 groups of Y chromosomes and alcoholism (P< 0.02, P<0.001, P<0.04). There were no discernible Y chromosome effects on ASPD.